Prefilled packages such as parenteral products are terminally sterilized to reduce or eliminate the risk of exposing persons and animals to potential pathogens contained therein. The pharmaceutical industry, medical profession and Food and Drug Administration (FDA) have generally taken the position that terminal sterilization of prefilled packages can only be achieved (outside of radiation treatment such as Gamma, E-beam or ultraviolet) by steam sterilization. In steam sterilization, a steam autoclave is generally used in the preferred method.
The use dry heat at temperatures of 100.degree. C. to &gt;130.degree. C. has been well documented (e.g., through testing done on pathogens such as bacillus sterothermophilous) as being unable to sterilize hard goods, packaging components and equipment such as parenteral manufacturing vessels. However, these documented tests are flawed in that they are not representative of actual sterilization. During these documented tests, the test micro organisms and/or pathogens were given direct exposure to the dry heat. In contrast, during actual steam sterilization procedures micro organisms and/or pathogens are not given direct exposure to dry heat, but are contained inside a prefilled package such as a syringe, vial, or cartridge. As the package is heated, the prefilled fluid or formulation inside the package vaporizes. This vapor produces a pressure and temperature which is lethal or cidal to pathogens. It has been the failure of the industry to understand this flaw in the understanding of the testing that has lead them to believe that a steam environment outside the prefilled package is a necessary requirement to produce the desired lethal or cidal effect on the pathogens inside the package.
The prior art discloses processes for producing parenteral products prefilled into sterile and non-sterile primary packages, then subjecting the prefilled packages to terminal sterilization by steam autoclaving with varying amounts of air over pressure used in conjunction with the steam. Prior to U.S. Pat. No. 4,718,463, to Jurgens et al. and U.S. Pat. No. 5,207,983, to Liebert et al., which are hereby incorporated by reference, the terminal sterilization of prefilled syringes and prefilled cartridges by steam autoclaving had not been successfully accomplished.
The patents to Jurgens et al. and Liebert et al. explored and addressed failures during sterilization by steam autoclaving of prefilled parenteral packages such as syringes and cartridges. These failures occurred for primarily four reasons:
First, the plunger would blow out due to an excessive pressure differential between the inside and outside of the barrel. During sterilization, a pressure differential would result from the combined vaporization of the formulation and expansion of the head space gas due to heat input, and insufficient pressure maintained outside the package in the sterilization vessel.
Second, the plunger would blow out due to inadequate allowances for plunger movement. During heating, a sufficient space must exist on the proximal side of the plunger to accommodate for expansion of the formulation and head space gas.
Third, the plunger may blow out due to a temporary low pressure spike during the cooling phase of the prefilled plastic syringes and cartridges. During cooling, the sterilization chamber pressure drops such that the pressure within the syringe is sufficiently higher than the chamber pressure. This pressure differential overcomes the frictional drag resistance between the plunger and the barrel thereby resulting in plunger movement and failure by the plunger blowing out the breech end of the barrel. This is a significant risk which was noted when using the method of Liebert et al., U.S. Pat. No. 5,207,983.
Fourth, the head space volume in the prefilled syringe or cartridge is too large causing a failure similar to inadequate reservations for plunger movement.
An understanding of the need to diminish the pressure differential between the chamber and the package interior was recognized by Jurgens et al., U.S. Pat. No. 4,718,463, which proposed maintenance of autoclave chamber pressure at least equal to the pressure inside the prefilled syringes. This condition, when all other aspects are under control, reduced the risk of plunger blow out.
Greater understanding of the relevant mechanisms for achieving successful terminal sterilization were demonstrated by Liebert et al., U.S. Pat. No. 5,207,983, by specifying an autoclave chamber pressure less than the pressure of the syringe contents. Additionally, the importance of head space volume and empty space at the proximal end of the barrel was also recognized and specified. Head space volume was specified as .ltoreq.10% by volume and empty space at the proximal end of the barrel, behind the plunger of 2% to 10%. Liebert et al. further identified the potential for terminal steam sterilization of glass syringes and cartridges that were not restricted by the amount of autoclave chamber over pressure as were the syringes and cartridges fabricated from plastic.
One of the drawbacks of the methods of the Jurgens et al. and Liebert et al. patents is the significant cost requirement. These methods require numerous mechanisms and conditions, such as a supply of Water For Injection, plant steam, stack water, a clean steam and its associated generator, a filtered air source and appropriate power feed, for operation of the steam autoclave. In addition to these mechanisms and conditions, the autoclave also required state of the art programmable control systems. The control systems must have the capability of purging residual air, accurately regulate heating rate based on load temperature, chamber pressure, temperature range during exposure, cooling rate, pressure ramp and air over pressure. Add to these requirements the hardware necessary, such as the jacketed vessel circulation pump(s), heat exchangers, process water and WFI plumbing, air lines, suitable waste water collection system and temperature monitoring equipment such as RTDs or thermocouples it is clear that a tremendous investment is necessary. While the present invention can be performed in an expensive autoclave chamber, it reduces the expense necessary by being usable in a much simpler and more economical chamber.